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Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32–72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.

Abstract Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0–1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.

Nivolumab plus ipilimumab (NIVO+IPI) has a long‐term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second‐line treatment in patients with mRCC. The data used in this multi‐institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor‐tyrosine kinase inhibitor. Associations between PRD and progression‐free survival of second‐line treatment (PFS), progression‐free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male‐dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176–2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649–6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040–5.437; p < 0.001). Before starting second‐line therapy, patients with PRD tended to have a poor performance status compared with non‐PRD patients and a higher IMDC risk. Second‐line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first‐line treatment was associated with poor clinical course, even with second‐line therapy. Primary resistant disease in patients with mRCC receiving NIVO+IPI as first‐line treatment was associated with poor clinical course, even with second‐line therapy. Second‐line VEGFR‐TKI treatment did not influence the survival outcomes of patients with PRD.

Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second‐line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second‐line nab‐paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first‐line chemotherapy were enrolled. Subjects received nab‐paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression‐free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next‐generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor‐infiltrating lymphocytes were applied to explore potential biomarkers. Twenty‐six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60–278 days). The median OS was 442 days (about 14.7 months, 95% CI 298–586 days). Grade 3 treatment‐related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD‐L1 and high proportions of CD8+ T‐cell infiltration were correlated with improved clinical outcome. Nab‐paclitaxel plus sintilimab is a potentially effective and tolerable second‐line regimen for advanced BTC that deserves to be studied in large‐scale trials. PD‐L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction. Second‐line treatment for biliary tract cancer (BTC) is very limited. This phase 2 trial suggested nab‐paclitaxel plus sintilimab was effective and tolerable in a second‐line setting for advanced BTC. The study met the primary efficacy end point, with an objective response rate of 26.9%. Biomarker analysis indicated that positive programmed cell death ligand 1 and high proportions of CD8+ T‐cell infiltration were potential biomarkers for efficacy prediction.

Background We previously reported results of a pooled analysis of two zanubrutinib studies in relapsed or refractory (R/R) MCL showing better survival outcomes when zanubrutinib is used in second‐line versus later‐line. Here, we present an updated pooled analysis with a longer follow‐up of 35.2 months. Methods Data were pooled from two studies—BGB‐3111‐AU‐003 (NCT02343120) and BGB‐3111‐206 (NCT03206970) of zanubrutinib in R/R MCL. The patients were divided into two groups based on the treatment line of zanubrutinib: the second‐line and the later‐line group. The inverse propensity score weighting method was used to balance the baseline covariates between the groups. The primary outcome was overall survival (OS). Secondary outcomes included progression‐free survival (PFS), PFS, and OS rates, objective response rate (ORR), duration of response (DOR), and safety. Results Among 112 pooled patients, 41 (36.6%) patients received zanubrutinib as second‐line and 71 (63.4%) patients as later‐line therapy. After weighting, OS was significantly improved in the second‐line versus later‐line group (HR, 0.459 [95% CI: 0.215, 0.98]; p = 0.044) with median OS not estimable in both groups. The PFS was similar between the two groups (HR, 0.78 [95% CI: 0.443, 1.373]; p = 0.389) but with numerically longer median PFS in the second‐line versus later‐line group (27.8 vs. 22.1 months). ORR was numerically higher in the second‐line versus later‐line (88.6% vs. 85.7%), and DOR was similar between the two groups (25.2 vs. 25.1 months). Zanubrutinib showed a similar safety profile in both groups. Conclusion Zanubrutinib in second‐line treatment was associated with significantly improved OS compared with later‐line treatment of R/R MCL. This pooled analysis of two studies of zanubrutinib examined its efficacy and safety in the treatment of patients with recurrent/relapsed mantle cell lymphoma (MCL) in two different settings—second‐line and later‐line with long‐term follow‐up. This analysis showed that patients receiving zanubrutinib in the second‐line had significantly better overall survival than those who received it in the later‐line. The finding suggests that earlier use of zanubrutinib in the treatment line may lead to better outcomes in patients with recurrent/relapsed MCL.

Background Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin‐dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. Methods This Phase 2 open‐label study enrolled patients with metastatic PDAC who progressed after 1–2 prior therapies. Patients were enrolled in a safety lead‐in (abemaciclib plus galunisertib) followed by a 2‐stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib‐containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression‐free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. Results One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4–1.8), 1.8 months (95% CI: 1.3–1.9), and 3.3 months (95% CI: 1.1–5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. Conclusion In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC. Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.

Introduction The global target for 2020 is that ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) will achieve viral load suppression (VLS). We examined VLS and its determinants among adults receiving ART for at least four months. Methods We analysed data from the population‐based HIV impact assessment (PHIA) surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe (2015 to 2017). PHIA surveys are nationally representative, cross‐sectional household surveys. Data collection included structured interviews, home‐based HIV testing and laboratory testing. Blood samples from PLHIV were analysed for HIV RNA, CD4 counts and recent exposure to antiretroviral drugs (ARVs). We calculated representative estimates for the prevalence of VLS (viral load <1000 copies/mL), nonsuppressed viral load (NVL; viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL) and rates of switching to second‐line ART (protease inhibitors present) among PLHIV aged 15 to 59 years who participated in the PHIA surveys in Eswatini, Lesotho, Malawi, Zambia and Zimbabwe, initiated ART at least four months before the survey and were receiving ART at the time of the survey (according to self‐report or ARV testing). We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second‐line ART. Results We included 9200 adults receiving ART of whom 88.8% had VLS and 11.2% had NVL including 8.2% who experienced VF and 3.0% who interrupted ART. Younger age, male sex, less education, suboptimal adherence, receiving nevirapine, HIV non‐disclosure, never having married and residing in Zimbabwe, Lesotho or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female sex, shorter ART duration, higher CD4 count and alcohol use were associated with lower odds for VF and higher odds for interrupted ART. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second‐line ART. Conclusions Countries are approaching global VLS targets for adults. Treatment support, in particular for younger adults, and people with higher CD4 counts, and switching of people to protease inhibitor‐ or integrase inhibitor‐based regimens may further reduce NVL prevalence.

Aims Second‐line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Although many patients receiving SLC have undergone gastrectomy, the impact of gastrectomy on SLC remains unclear. Patients and Methods The objective was to evaluate the impact of gastrectomy on SLC for AGC. A total of 290 eligible patients registered in two randomized phase III trials evaluating SLC for patients with AGC was classified into the prior gastrectomy group (PGG; n = 187) or the no gastrectomy group (NGG; n = 103). We compared overall survival (OS), progression‐free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety between these two groups. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). Results The PGG had better performance status (p = 0.001), more prior platinum agent (p < 0.001), and more frequent peritoneal metastasis (p = 0.006) than the NGG. The PGG had significantly better OS (13.8 vs. 9.3 mo; hazard ratio [HR]: 0.59; p < 0.001) and PFS (4.7 vs. 2.8 mo; HR: 0.58; p < 0.001) than the NGG. The PGG had significantly better adjusted OS (13.8 vs. 10.0 mo; IPTW HR: 0.66; p = 0.01) and adjusted PFS (4.3 vs. 3.2 mo; IPTW HR: 0.71; p = 0.027) than the NGG. No significant differences were observed in ORR and DCR. The incidence of Grade 3 or worse adverse events did not differ between the two groups except for a high incidence of anemia and diarrhea in the NGG. Conclusion Patients with previous gastrectomy are expected to have better survival outcomes when receiving second‐line irinotecan (IRI)‐based chemotherapy for AGC. In an analysis of two RCTs of IRI‐based second‐line chemotherapy for AGC, patients with prior gastrectomy had better OS and PFS than patients without prior gastrectomy. Furthermore, patients with prior gastrectomy had a better prognosis in OS and PFS adjusted for background factors as well.

This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine‐containing chemotherapy. Patients with unresectable or recurrent gastric cancer who experienced progression despite fluoropyrimidine‐containing treatment were studied. Nab‐paclitaxel was given i.v. at 260 mg/m2 on day 1 of each 21‐day cycle without anti‐allergic premedication until disease progression or study discontinuation. The primary endpoint was the overall response rate. The secondary endpoints were the disease control rate, progression‐free survival, overall survival, and safety. From April 2008 to July 2010, 56 patients were enrolled, 55 patients received the study treatment, and 54 patients were evaluable for responses. According to an independent review committee, the overall response rate was 27.8% (15/54; 95% confidence interval [CI], 16.5–41.6) and the disease control rate was 59.3% (32/54; 95% CI, 45.0–72.4). One patient had a complete response. The median progression‐free survival and overall survival were 2.9 months (95% CI, 2.4–3.6) and 9.2 months (95% CI, 6.9–11.4), respectively. The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%), and peripheral sensory neuropathy (23.6%). There were no treatment‐related deaths. Nab‐paclitaxel, given every 3 weeks, showed promising activity against previously treated unresectable or recurrent gastric cancers, with well‐tolerated toxicities. (Trial registration, ClinicalTrials.gov: NCT00661167). This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine‐containing chemotherapy. This regimen showed promising activity, with well‐tolerated toxicities.